tbuckley/cabot-search huggingface dataset:
Synovial Inflammatory Pathways Characterize <scp>Anti‐TNF</scp>–Responsive Rheumatoid Arthritis Patients
Authors: Jing Wang, Donna Conlon, Felice Rivellese, Alessandra Nerviani, Myles J. Lewis, William Housley, Marc C. Levesque, Xiaohong Cao, Carolyn Cuff, Andrew Long, Costantino Pitzalis, Melanie C. Ruzek
Journal: Arthritis & Rheumatology (2022)

This study was undertaken to understand the mechanistic basis of response to anti-tumor necrosis factor (anti-TNF) therapies and to determine whether transcriptomic changes in the synovium are reflected in peripheral protein markers.Synovial tissue from 46 rheumatoid arthritis (RA) patients was profiled with RNA sequencing before and 12 weeks after treatment with anti-TNF therapies. Pathway and gene signature analyses were performed on RNA expression profiles of synovial biopsies to identify mechanisms that could discriminate among patients with a good response, a moderate response, or no response, according to the American College of Rheumatology (ACR)/EULAR response criteria. Serum proteins encoded by synovial genes that were differentially expressed between ACR/EULAR response groups were measured in the same patients.Gene signatures predicted which patients would have good responses, and pathway analysis identified elevated immune pathways, including chemokine signaling, Th1/Th2 cell differentiation, and Toll-like receptor signaling, uniquely in good responders. These inflammatory pathways were correspondingly down-modulated by anti-TNF therapy only in good responders. Based on cell signature analysis, lymphocyte, myeloid, and fibroblast cell populations were elevated in good responders relative to nonresponders, consistent with the increased inflammatory pathways. Cell signatures that decreased following anti-TNF treatment were predominately associated with lymphocytes, and fewer were associated with myeloid and fibroblast populations. Following anti-TNF treatment, and only in good responders, several peripheral inflammatory proteins decreased in a manner that was consistent with corresponding synovial gene changes.Collectively, these data suggest that RA patients with robust responses to anti-TNF therapies are characterized at baseline by immune pathway activation, which decreases following anti-TNF treatment. Understanding mechanisms that define patient responsiveness to anti-TNF treatment may assist in development of predictive markers of patient response and earlier treatment options.
Covid-19: Recovery trial set to lose funding as proposal to examine flu drugs is rejected
Authors: Elisabeth Mahase
Journal: BMJ (2022)

Covid-19: Recovery trial set to lose funding as proposal to examine flu drugs is rejected Elisabeth MahaseFunding for the UK's Randomised Evaluation of Covid-19 Therapy (Recovery) trial-which has been instrumental in finding cheap and effective covid-19 treatments-is to end in October, the trial's co-leads have said.1
Nuclear Magnetic Resonance Metabolomic Profiling and Urine Chemistries in Incident Kidney Stone Formers Compared with Controls
Authors: Charat Thongprayoon, Ivan Vuckovic, Lisa E. Vaughan, Slobodan Macura, Nicholas B. Larson, Matthew R. D’Costa, John C. Lieske, Andrew D. Rule, Aleksandar Denic
Journal: Journal of the American Society of Nephrology (2022)

Background: The urine metabolites and chemistries that contribute to kidney stone formation are not fully understood. This study examined differences between the urine metabolic and chemistries profiles of first-time stone formers and controls. Methods: High resolution 1H-nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was performed in 24-hour urines from a prospective cohort of 418 first-time symptomatic kidney stone formers and 440 controls. Forty-eight NMR-quantified metabolites in addition to 12 standard urine chemistries were assayed. Analysis of covariance was used to determine the association of stone former status with urine metabolites or chemistries after adjusting for age and sex and correcting for false discovery rate. Gradient boosted machine methods with nested cross-validation were applied to predict stone former status. Results: Among the standard urine chemistries, stone formers had lower urine oxalate and potassium and higher urine calcium, phosphate, and creatinine. Among NMR urine metabolites, stone formers had lower hippuric acid, trigonelline, 2-furoylglycine, imidazole, and citrate, and higher creatine and alanine. A cross-validated model using urine chemistries, age, and sex yielded a mean AUC of 0.760 (95% CI: 0.728 to 0.792). A cross-validated model using urine chemistries, NMR-quantified metabolites, age, and sex did not meaningfully improve the discrimination (mean AUC:0.776 (95% CI: 0.745 to 0.807). In this combined model, among the top 10 discriminating features 4 were urine chemistries and 6 NMR-quantified metabolites. Conclusion: Although NMR-quantified metabolites did not improve discrimination, several urine metabolic profiles were identified that may improve understanding of kidney stone pathogenesis.
Effectiveness of automated alerting system compared to usual care for the management of sepsis
Authors: Zhongheng Zhang, Lin Chen, Ping Xu, Qing Wang, Jianjun Zhang, Kun Chen, Casey M. Clements, Leo Anthony Celi, Vitaly Herasevich, Yucai Hong
Journal: npj Digital Medicine (2022)

There is a large body of evidence showing that delayed initiation of sepsis bundle is associated with adverse clinical outcomes in patients with sepsis. However, it is controversial whether electronic automated alerts can help improve clinical outcomes of sepsis. Electronic databases are searched from inception to December 2021 for comparative effectiveness studies comparing automated alerts versus usual care for the management of sepsis. A total of 36 studies are eligible for analysis, including 6 randomized controlled trials and 30 non-randomized studies. There is significant heterogeneity in these studies concerning the study setting, design, and alerting methods. The Bayesian meta-analysis by using pooled effects of non-randomized studies as priors shows a beneficial effect of the alerting system (relative risk [RR]: 0.71; 95% credible interval: 0.62 to 0.81) in reducing mortality. The automated alerting system shows less beneficial effects in the intensive care unit (RR: 0.90; 95% CI: 0.73-1.11) than that in the emergency department (RR: 0.68; 95% CI: 0.51-0.90) and ward (RR: 0.71; 95% CI: 0.61-0.82). Furthermore, machine learning-based prediction methods can reduce mortality by a larger magnitude (RR: 0.56; 95% CI: 0.39-0.80) than rule-based methods (RR: 0.73; 95% CI: 0.63-0.85). The study shows a statistically significant beneficial effect of using the automated alerting system in the management of sepsis. Interestingly, machine learning monitoring systems coupled with better early interventions show promise, especially for patients outside of the intensive care unit.
Diagnosis and Management of Hyponatremia
Authors: Horacio J. Adrogué, Bryan M. Tucker, Nicolaos E. Madias
Journal: JAMA (2022)

<h3>Importance</h3> Hyponatremia is the most common electrolyte disorder and it affects approximately 5% of adults and 35% of hospitalized patients. Hyponatremia is defined by a serum sodium level of less than 135 mEq/L and most commonly results from water retention. Even mild hyponatremia is associated with increased hospital stay and mortality. <h3>Observations</h3> Symptoms and signs of hyponatremia range from mild and nonspecific (such as weakness or nausea) to severe and life-threatening (such as seizures or coma). Symptom severity depends on the rapidity of development, duration, and severity of hyponatremia. Mild chronic hyponatremia is associated with cognitive impairment, gait disturbances, and increased rates of falls and fractures. In a prospective study, patients with hyponatremia more frequently reported a history of falling compared with people with normal serum sodium levels (23.8% vs 16.4%, respectively;<i>P</i> &lt; .01) and had a higher rate of new fractures over a mean follow-up of 7.4 years (23.3% vs 17.3%;<i>P</i> &lt; .004). Hyponatremia is a secondary cause of osteoporosis. When evaluating patients, clinicians should categorize them according to their fluid volume status (hypovolemic hyponatremia, euvolemic hyponatremia, or hypervolemic hyponatremia). For most patients, the approach to managing hyponatremia should consist of treating the underlying cause. Urea and vaptans can be effective treatments for the syndrome of inappropriate antidiuresis and hyponatremia in patients with heart failure, but have adverse effects (eg, poor palatability and gastric intolerance with urea; and overly rapid correction of hyponatremia and increased thirst with vaptans). Severely symptomatic hyponatremia (with signs of somnolence, obtundation, coma, seizures, or cardiorespiratory distress) is a medical emergency. US and European guidelines recommend treating severely symptomatic hyponatremia with bolus hypertonic saline to reverse hyponatremic encephalopathy by increasing the serum sodium level by 4 mEq/L to 6 mEq/L within 1 to 2 hours but by no more than 10 mEq/L (correction limit) within the first 24 hours. This treatment approach exceeds the correction limit in about 4.5% to 28% of people. Overly rapid correction of chronic hyponatremia may cause osmotic demyelination, a rare but severe neurological condition, which can result in parkinsonism, quadriparesis, or even death. <h3>Conclusions and Relevance</h3> Hyponatremia affects approximately 5% of adults and 35% of patients who are hospitalized. Most patients should be managed by treating their underlying disease and according to whether they have hypovolemic, euvolemic, or hypervolemic hyponatremia. Urea and vaptans can be effective in managing the syndrome of inappropriate antidiuresis and hyponatremia in patients with heart failure; hypertonic saline is reserved for patients with severely symptomatic hyponatremia.
The Highs and Lows of Potassium Intake in CKD—Does One Size Fit All?
Authors: Andrew S. Terker, Turgay Saritas, Alicia A. McDonough
Journal: Journal of the American Society of Nephrology (2022)

Electrolyte management is integral to the nephrological care of patients with CKD. Clinicians routinely face potassium derangements in settings of kidney dysfunction; hyperkalemia is of high concern given the potential for life-threatening cardiac arrhythmias. This concern drives recommendations of
Echocardiographic Measures of Left Atrial Function and Size and Incident Dementia
Authors: Gianluca Rigatelli, Marco Zuin
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination
Authors: Jinyi Tang, Cong Zeng, Thomas M. Cox, Chaofan Li, Young Min Son, In Su Cheon, Yue Wu, Supriya Behl, Justin J. Taylor, Rana Chakaraborty, Aaron J. Johnson, Dante N. Shiavo, James P. Utz, Janani S. Reisenauer, David E. Midthun, John J. Mullon, Eric S. Edell, Mohamad G. Alameh, Larry Borish, William G. Teague, Mark H. Kaplan, Drew Weissman, Ryan Kern, Haitao Hu, Robert Vassallo, Shan-Lu Liu, Jie Sun
Journal: Science Immunology (2022)

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19-vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.
Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses
Authors: Juan Yan, Yuedan Chen, Amish J. Patel, Sarah Warda, Cindy J. Lee, Briana G. Nixon, Elissa W.P. Wong, Miguel A. Miranda-Román, Ning Yang, Yi Wang, Mohini R. Pachai, Jessica Sher, Emily Giff, Fanying Tang, Ekta Khurana, Sam Singer, Yang Liu, Phillip M. Galbo, Jesper L.V. Maag, Richard P. Koche, Deyou Zheng, Cristina R. Antonescu, Liang Deng, Ming O. Li, Yu Chen, Ping Chi
Journal: Journal of Clinical Investigation (2022)

Immune checkpoint blockade (ICB) has demonstrated clinical success in "inflamed" tumors with substantial T cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell–intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrated that inactivation of the polycomb-repressive complex 2 (PRC2) core components embryonic ectoderm development (EED) or suppressor of zeste 12 homolog (SUZ12), a prevalent genetic event in malignant peripheral nerve sheath tumors (MPNSTs) and sporadically in other cancers, drove a context-dependent immune-desert TME. PRC2 inactivation reprogramed the chromatin landscape that led to a cell-autonomous shift from primed baseline signaling-dependent cellular responses (e.g., IFN-γ signaling) to PRC2-regulated developmental and cellular differentiation transcriptional programs. Further, PRC2 inactivation led to diminished tumor immune infiltrates through reduced chemokine production and impaired antigen presentation and T cell priming, resulting in primary resistance to ICB. Intratumoral delivery of inactivated modified vaccinia virus Ankara (MVA) enhanced tumor immune infiltrates and sensitized PRC2-loss tumors to ICB. Our results identify molecular mechanisms of PRC2 inactivation–mediated, context-dependent epigenetic reprogramming that underline the immune-desert phenotype in cancer. Our studies also point to intratumoral delivery of immunogenic viruses as an initial therapeutic strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB.
<i>Vital Signs: </i>Drug Overdose Deaths, by Selected Sociodemographic and Social Determinants of Health Characteristics — 25 States and the District of Columbia, 2019–2020
Authors: Mbabazi Kariisa, Nicole L. Davis, Sagar Kumar, Puja Seth, Christine L. Mattson, Farnaz Chowdhury, Christopher M. Jones
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Drug overdose deaths increased approximately 30% from 2019 to 2020 in the United States. Examining rates by demographic and social determinants of health characteristics can identify disproportionately affected populations and inform strategies to reduce drug overdose deaths.
Emerging Insights into Glomerular Vascular Pole and Microcirculation
Authors: Michael S. Goligorsky
Journal: Journal of the American Society of Nephrology (2022)

The glomerular vascular pole is the gate for the afferent and efferent arterioles and mesangial cells and a frequent location of peripolar cells with an unclear function. It has been studied in definitive detail for &gt;30 years, and functionally interrogated in the context of signal transduction from the macula densa to the mesangial cells and afferent arteriolar smooth muscle cells from 10 to 20 years ago. Two recent discoveries shed additional light on the vascular pole, with possibly far-reaching implications. One, which uses novel serial section electron microscopy, reveals a shorter capillary pathway between the basins of the afferent and efferent arterioles. Such a pathway, when patent, may short-circuit the multitude of capillaries in the glomerular tuft. Notably, this shorter capillary route is enclosed within the glomerular mesangium. The second study used anti-Thy1.1–induced mesangiolysis and intravital microscopy to unequivocally establish in vivo the long-suspected contractile function of mesangial cells, which have the ability to change the geometry and curvature of glomerular capillaries. These studies led me to hypothesize the existence of a glomerular perfusion rheostat, in which the shorter path periodically fluctuates between being more and less patent. This action reduces or increases blood flow through the entire glomerular capillary tuft. A corollary is that the GFR is a net product of balance between the states of capillary perfusion, and that deviations from the balanced state would increase or decrease GFR. Taken together, these studies may pave the way to a more profound understanding of glomerular microcirculation under basal conditions and in progression of glomerulopathies.
Geospatial Immune Heterogeneity Reflects the Diverse Tumor–Immune Interactions in Intrahepatic Cholangiocarcinoma
Authors: Youpei Lin, Lihua Peng, Liangqing Dong, Dongbing Liu, Jiaqiang Ma, Jian Lin, Xiaofang Chen, Penghui Lin, Guohe Song, Mao Zhang, Yuming Liu, Junhua Rao, Chen Wei, Ye Lu, Shu Zhang, Guangyu Ding, Zhenyu Peng, Haorong Lu, Xiaoying Wang, Jian Zhou, Jia Fan, Kui Wu, Qiang Gao
Journal: Cancer Discovery (2022)

Intrahepatic cholangiocarcinoma (iCCA) exhibits extensive intratumoral heterogeneity and an extremely high mortality rate. Here, we performed whole-exome sequencing, RNA sequencing, T-cell receptor (TCR) sequencing, and multiplexed immunofluorescence on 207 tumor regions from 45 patients with iCCA. Over half of iCCA displayed intratumoral heterogeneity of immune infiltration, and iCCA were classified into sparsely, heterogeneously, and highly infiltrated subgroups with distinct immunogenomic characteristics. Sparsely infiltrated tumors displayed active copy-number loss of clonal neoantigens, and heterogeneous immune infiltration played an important role in the subclonal evolution across tumor subregions. Highly infiltrated tumors were characterized by extensive immune activation and a similar TCR repertoire across tumor subregions, but counteracted with T-cell exhaustion and pervasive antigen presentation defects. Notably, FGFR2 mutations and fusions correlated with low mutation burden and reduced immune infiltration. Our work delineated the dynamic tumor-immune interactions and developed a robust classification system to divide patients with iCCA into high and low immune evasion groups with different prognoses. This study elucidates the impact of spatial immune heterogeneity upon tumor evolution of iCCA and reveals distinct immune evasion mechanisms developed in different immune microenvironments, which can be exploited for the development of personalized immunotherapy strategies. This article is highlighted in the In This Issue feature, p. 2221.
Single-Cell Transcriptome Profiling Reveals Intratumoral Heterogeneity and Molecular Features of Ductal Carcinoma <i>In Situ</i>
Authors: Momoko Tokura, Jun Nakayama, Marta Prieto-Vila, Sho Shiino, Masayuki Yoshida, Tomofumi Yamamoto, Naoaki Watanabe, Shin Takayama, Yutaka Suzuki, Koji Okamoto, Takahiro Ochiya, Takashi Kohno, Yasushi Yatabe, Akihiko Suto, Yusuke Yamamoto
Journal: Cancer Research (2022)

Abstract Ductal carcinoma in situ (DCIS) is a precursor to invasive breast cancer. The frequency of DCIS is increasing because of routine mammography; however, the biological features and intratumoral heterogeneity of DCIS remain obscure. To address this deficiency, we performed single-cell transcriptomic profiling of DCIS and invasive ductal carcinoma (IDC). DCIS was found to be composed of several transcriptionally distinct subpopulations of cancer cells with specific functions. Several transcripts, including long noncoding RNAs, were highly expressed in IDC compared with DCIS and might be related to the invasive phenotype. Closeness centrality analysis revealed extensive heterogeneity in DCIS, and the prediction model for cell-to-cell interactions implied that the interaction network among luminal cells and immune cells in DCIS was comparable with that in IDC. In addition, transcriptomic profiling of HER2+ luminal DCIS indicated HER2 genomic amplification at the DCIS stage. These data provide novel insight into the intratumoral heterogeneity and molecular features of DCIS, which exhibit properties similar to IDC. Significance: Investigation of the molecular features of ductal carcinoma in situ at single cell resolution provides new insights into breast cancer biology and identifies candidate therapeutic targets and diagnostic biomarkers.